Amlodipine is a calcium channel blocker developed for the treatment of hypertension and other medical indications as disclosed in U.S. Pat. No. 4,572,909 and U.S. Pat. No. 4,879,303. Its chemical name is 3-ethyl-5-methyl-(++2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate.
Amlodipine is marketed as the monobenzenesulfonate salt, amlodipine besylate under the trade name Norvasc® or Istin®. It is available as oral tablets in strengths of 2.5 mg, 5 mg and 10 mg. The inactive ingredients in the Norvasc® tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate and magnesium stearate.
Amlodipine besylate is slightly soluble in water and has an absolute bioavailability of 64-90%.
Irbesartan is described in Bernhart et al., U.S. Pat. No. 5,270,317, incorporated herein by reference.
Irbesartan, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Its chemical name is 2-n-butyl-4-spirocyclopentane-1-[(2′-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one.
Irbesartan is marketed by under the trade name Aprovel® or Karvea®.
Irbesartan is insoluble in water. Irbesartan has a parabolic pH solubility profile in aqueous medium with minimum solubility between pH 2.0 and 6.0 and maximum solubility in 0.1 N HCl and pH 7.5 phosphate buffer.
It is often desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms.
However, a combination of active ingredients is not without drawbacks.
Certain physical properties of the drugs and specifically stability, present a challenge in developing formulations suitable for preparing a tablet having reduced levels of total impurities on long term stability.
Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. It is also a sticky and abrasive material.
These properties make it difficult to formulate an effective amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties. In addition, irbesartan has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press.
The very low aqueous solubility of irbesartan also presents a challenge, since only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release.
The addition of a second active ingredient such as amlodipine besilate, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to problems such as tableting or uniformity of dosage units.
In addition, the stability of a composition might be compromised due to incompatibility of an active with an essential excipient or even between a second active itself.
Concerning formulations containing Amlodipine besilate alone, WO 2006/059217 discloses that amlodipine is highly hygroscopic and absorbs moisture, which leads to degradation. One of the major routes of degradation is via a catalytic oxidative process, which is pH dependent. One of the major degradation products known in the art is 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate and called Impurity D.
WO2003/051364 discloses Amlodipine besilate tablets with improved stability of the active ingredient and reduced in weight containing microcrystalline cellulose, a lubricant and a disintegrating agent and the process for the preparation of said tablets.
WO2008/062435 discloses a stable solid dosage form of amlodipine besylate comprising polyols and having reduced levels of total impurities on stability and especially impurity D.
Concerning formulations containing Irbesartan, EP747050 from Sanofi discloses pharmaceutical composition under tablets comprising Irbesartan alone or in combination with a diuretic compound such as Hydrochlorothiazide (HCTZ) prepared by a process comprising mixing an extragranular composition with granules comprising either irbesartan alone or the two active principles in the presence of lactose and an antiadherent such as silicon dioxide. No problem of stability is raised.
WO2005/070762 from Sepracor discloses oral formulation under capsules comprising the combination of S-amlodipine and Irbesartan obtained by simple mixing about 25 wt % of the two active principles together in the presence of corn starch and about 65 wt % of lactose. No problem of stability is raised.
Thus, there is no known stable solid dosage form comprising the specific combination of Irbesartan and Amlodipine besilate.
In addition to stability, when formulating solid fixed dose combination, the objective is to provide a patient-convenient combination dosage form of active ingredients that is bioequivalent to the corresponding free-combination of the same active ingredients.
As used herein, “fixed-dose-combination or FDC” refers to a combination of two drugs or active ingredients presented in a single dosage unit such as a tablet or oral dosage form.
Further as used herein, “free-combination” refers to a combination of two drugs or active ingredients dosed simultaneously but as two dosage units.
As a result of these complex biopharmaceutical properties, development of a fixed-combination dosage form of irbesartan and amlodipine besilate that is bio equivalent to a free-combination thereof is challenging.
Accordingly, a fixed-combination solid dosage formulation of Irbesartan and amlodipine besilate that is stable and bioequivalent to the corresponding free-combination would be desirable.
One other challenge faced is homogenity of Amlodipine in a lubricated blend as the content of Amlodipine in the total tablet weight should be very low compared to the high amount of irbesartan.
The object of the present invention is to alleviate at least partly the above mentioned drawbacks.